Melanoma remains the deadliest form of skin cancer, with a five year survival of only 15%. The advent of drugs specifically targeting mutated BRAF has represented a major improvement in melanoma patient care. Yet, these therapies are hampered by the development of resistance, and are applicable exclusively to patients with mutated BRAF. Here we will dissect the role and mechanisms of a novel therapy specifically targeting ERBB3 and Notch1 by novel, selective neutralizing antibodies that is preclinically effective in both BRAF mutant and wild type tumors. We have shown that 70% of melanomas concurrently re-activate Notch1 and ERBB3[1] and that blockade of both receptor signaling by either a ?-secretase inhibitor (GSI) and lapatinib, or by specific silencing of Notch1 and ERBB3, results in melanoma tumor growth arrest and partial tumor regression of both wild type and BRAF mutated melanomas[1]. ERBB3 up-regulation is also involved in BRAF inhibitors resistance; and promotes melanoma metastasis. Whereas Notch inhibition enhances the efficacy of BRAF inhibitors. Hence, a therapy targeting Notch1 and ERBB3 could overcome BRAF inhibitor resistance; and extend to BRAF wild type tumors, providing therapeutic benefits to a majority of melanoma patients. A limitation of p an-Notch inhibitors such as GSIs is the development of gastrointestinal side effects due to the disruption of both Notch1 and Notch2 in the stem cells in the intestinal crypts. Lapatinib, while generally considered well tolerated, can also lead to gastrointestinal toxicities. Hence, a combination therapy of GSI/lapatinib, while conceivable, may require a thorough clinical management. Alternatively, a more targeted approach would likely benefit from reduced or no toxicities. Specific inhibition of Notch1 and ERBB3 by shRNA recapitulates the effects observed with GSI/lapatinib. We therefore developed a selective Notch1 (anti-N1) neutralizing antibody that does not affect the activity of other Notch receptors, in particular Notch2; and combined it with a selective ERBB3 neutralizing antibody (anti-B3) with anti-tumor properties against several cancers, including melanoma. Our data show that: 1) the antibody combination reduces cell survival by 70% versus 10% or either antibody alone; 2) The antibody combination prevents the rewiring of compensatory survival pathways activated by the single treatment. 3) anti- N1 and anti-B3 restore sensitivity to vemurafenib better than single antibody alone. We have therefore hypothesized that selective inhibition of both Notch1 and ERBB3 provides a safe, novel therapeutic approach to treat a wide range of melanoma patients regardless of the tumor genetic drivers. We will 1) determine the efficacy of the antibody combination in relevant Patient Derived Xenograft Models harboring wild type and mutated BRAF and either sensitive or resistant to vemurafenib; and 2) assess the adaptive kinome responses dictated by the antibody combination through phosphoproteomics on PDX tumors treated with the various antibody combination. We aim at defining the mechanisms underlying the therapeutic efficacy of Notch1 and ERBB3 inhibition and at identifing early markers of resistance to provide tools to follow drug response in patients.